Our objective is to identify genetic modulators of risk, prognosis and response to therapy for squamous cell carcinoma of the head and neck (SCCHN). We will employ two basic study designs to achieve three aims: a case control study to identify single nucleotide polymorphisms (SNPs) associated with SCCHN risk (Aim 1), and a patient cohort study to identify SNPs associated with progression free survival (PFS)(Aim 2) and treatment response (Aim 3), with a focus on platinum-based therapy. Our large specimen collection with over 1000 controls and 750 SCCHN cases to date with detailed clinical, pathologic and survival data for cases and demographic and risk factor data for all subjects provides us the unique ability to carry out these studies. DNA repair pathway genes have been implicated in both SCCHN risk and response to therapy. Preliminary data from our current SPORE study are consistent with other recent reports that show reduced DNA repair capacity, mediated by nucelotide excision repair (NER), may be associated with PFS in platinum-treated cases. We have recently expanded our genotyping analysis to a comprehensive 384 single nucleotide polymorphism (SNP) panel that includes all of the gene members of the NER pathway. In a preliminary haplotype association analysis, we have identified several gene haplotypes associated with either enhanced or reduced PFS in platinum-treated cases. Complementary to this hypothesis-driven candidate gene approach, genome wide association studies (GWAS) can identify new susceptibility genes without making a priori biological assumptions. We plan to design a 1536 SNP panel by implementing a hybrid strategy for SNP selection incorporating both candidate DNA repair pathway and cell cycle genes and a noncandidate gene approach based on emerging data from ongoing phase I GWAS studies. This integrated approach applied toward the selection of genetic variants in a large sample size provides the opportunity to identify and characterize novel genetic biomarkers of susceptibility, prognosis and prediction of therapeutic response. We will use SNP- and haplotype-based approaches in our evaluation of the role of genetic factors and their interactions with the environment in SCCHN risk and disease outcome.